Articular cartilage has a limited intrinsic ability to heal. For this reason, orthopaedic management of these lesions remains a persistent problem for the orthopedist and patient. The importance of treating injury to articular cartilage is underscored by the fact that several million people are affected in the United States alone by cartilage damage. (See Praemer A, Furner S, Rice D P. Musculoskeletal conditions in the United States. American Academy of Orthopaedic Surgeons 1999 p. 34-9). Focal lesions of articular cartilage can progress to more widespread cartilage destruction and arthritis that is disabling. Thus, numerous procedures have been developed in an attempt to treat these lesions and halt or slow the progression to diffuse arthritic changes. (See Browne J E, Branch T P. Surgical alternatives for treatment of articular cartilage leasions. J Am Acad Orthop Surg 2000; 8(3):180-9).
Surgical procedures to restore articular cartilage include debridement, abrasion arthroplasty, microfracturing, autologous chondrocyte transplantation and osteoarticular transfer. (Browne J E, Anderson A F, Arciero R, Mandelbaum B, Moseley J B, Micheli L J, Fu F, Erggelet C. Clinical outcome of autologous chondrocyte implantation at 5 years in US subjects. Clinical Orthopaedics and Related Research 2005; 436:237-245; Magnussen R A, Dunn W R, Carey J L, Spindler K P. Treatment of focal articular cartilage defects in the knee: a systematic review. Clinical Orthopaedics and Related Research 2008; 466:952-96). At present, none of these techniques have been able to restore a normal cartilaginous surface and have suffered from poor integration with the surrounding normal articular cartilage. Frequently, the repair tissue has inferior biochemical and biomechanical properties.
Current tissue engineering methods are aimed at filling the cartilage defects with cells or scaffolds alone, or in combination with one another. (Kang S W, Jeon O, Kim B S. Poly(lactic-co-glycolic acid) microspheres as an injectable scaffold for cartilage tissue engineering. Tissue Engineering 2005; 11:438-447; Kuo C K, Li W J, Mauck R L, Tuan R S. Cartilage tissue engineering: its potential and uses. Current Opinion in Rheumatology 2006; 18:64-73). However, it appears that the absence of cells leads to a poor quality reparative tissue.
Autologous chondrocytes are FDA approved, but of major concern is the limited proliferative capacity of differentiated chondrocytes (Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A. Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects. Matrix Biology 2002; 21:449-459). Long-term studies in patients have demonstrated that treated defects are filled with fibrocartilage, which may account for the poor mechanical stability. (Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, Jobanputra P, Waugh N. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation. Health Technology Assessment 2005; 9:1-8). Therefore, adult stem cells have been sought as an alternative cell source.
Mesenchymal stem cells (MSCs) are multipotent cells that are capable of differentiating into osteoblasts, chondrocytes, adipocytes, tenocytes, myoblasts, and neural cell lineages. (Pittenger M F, Mackay A M, Beck S C, Jaiswal R K, Douglas R, Mosca J D, Moorman M A, Simonetti D W, Craig S, Marshak D R. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284:143-147). From a small, bone marrow aspirate obtained from adults, MSCs can be isolated, readily expanded due to their proliferative capacity, and characterized. (Friedenstein A, Chailakhyan R, Gerasimov U V. Bone Marrow Osteogenic Stem Cells: In Vitro Cultivation and Transplantation in Diffusion Chambers. Cell Tissue Kinet 1987; 20:263-72; Haynesworth S, Baber M, Caplan A. Cell Surface Antigens on Human Marrow-Derived Mesenchymal Stem Cells are Detected by Monoclonal Antibodies. J Cell Physiol 1992; 138:8-16). In vitro and in vivo analyses have demonstrated that culture expanded MSCs can maintain the capacity to differentiate and proliferate after extensive passaging (Jaiswal N, Haynesworth S E, Caplan A I, Bruder S P. Osteogenic differentiation of purified culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem 1997; 64:295-312; Kadiyala S, Jaiswal N, Bruder S P. Culture-expanded, bone marrow-derived mesenchymal stem cells can regenerate a critical-sized segmental bone defect. Tissue Engineering 1997; 3:173-185; Rickard D J, Sullivan T A, Shenker B J, Leboy P S, Kazhdan I. Induction of rapid osteoblast differentiation in rat bone marrow stromal cell cultures by dexamethason and BMP-2. Dev Bio 1994; 161:218-228), suggesting that MSCs may be valuable as a readily available and abundant source of cells in the tissue engineering field. Allogeneic MSCs are also currently in clinical trials for various disorders or conditions. Therefore, an allogeneic MSC approach for tissue regeneration, e.g., cartilage tissue regeneration, could provide an excellent off-the-shelf therapy.
One way for a biodegradable scaffold to be successful is to make the material's rate of degradation commensurate with the growth of new tissue, e.g., cartilage. Ideally, the scaffold degrades at a rate to substantially maintain structural support during the initial stages of formation, but also allows space for continuous growth of new tissue. In addition to biochemical stability, the ideal synthetic tissue scaffold would also provide an appropriate chemical environment to facilitate cell and tissue growth, repair, and/or regeneration, and at the same time, provide the necessary biomechanical stability. It is therefore of great importance to develop a scaffold that will address these issues and provide the appropriate cues to support growth and differentiation of the stem cells, e.g., MSCs.